Our research goals have been to (1) understand the molecular basis of acquired drug resistance (2) comprehend how/why these changes occur;(3) search for them in clinical samples and (4) devise strategies to reduce or prevent their occurrence. Our efforts are increasingly directed at understanding how normal tissue might be affected by these agents and the extent to which they might or might not be protected by drug transporters such as P-glycoprotein and the half-transporter, ABCG2 We have also been investigating the role of drug transporters in affording the brain protection from chemotherapeutic agents. Driven in part by the recognition that as we develop more and more agents to be administered orally, we are developing agents that are likely to bypass the mechanisms that protect the brain and confer its status as a sanctuary, since many of the same transporters that protect line the GI tract, and drugs must be designed to bypass them if they are to be administered orally. We are conducting studies to hopefully understand the mechanisms that protect the brain and what might be the consequences of bypassing these barriers. We are doing this by both examining in vitro and in vivo models and through an exhaustive search of existing clinical data with the goal of further understanding this problem.